Research in Social and Administrative Pharmacy j (2013) j–j

Original Research

National antidepressant prescribing in children and adolescents with mental health disorders after an FDA boxed warning Manish Mittal, Ph.D.a,*,d, Donald L. Harrison, Ph.D., F.A.Ph.A.b, Michael J. Miller, R.Ph., Dr.P.H., F.A.Ph.A.c, Nancy C. Brahm, Pharm.D., M.S., B.C.P.P., C.G.P.c a

Health Economics and Outcomes Research, Abbvie, Dept. GMH1, AP31-1 NE, 1 North Waukegan Road, North Chicago, IL 60064, USA b University of Oklahoma Health Sciences Center, College of Pharmacy, Department of Pharmacy: Clinical and Administrative Sciences – Oklahoma City, OK, USA c University of Oklahoma Health Sciences Center, College of Pharmacy, Department of Pharmacy: Clinical and Administrative Sciences – Tulsa, OK, USA

Abstract Background: In October 2004, the U.S. Food and Drug Administration (FDA) issued a boxed warning about an increased risk of suicidality (i.e., suicidal ideation, behavior, or attempts) related to all antidepressants in children and adolescents. Objective: To describe national antidepressant prescribing patterns in children and adolescents before, during, and after the introduction of the FDA boxed warning. Methods: Cross-sectional data from the 2002–2009 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) were used to describe antidepressant prescribing patterns within a nationally-representative sample of 4035 physician visits for children and adolescents diagnosed with depression or other psychiatric disorder(s) [i.e., anxiety disorders or attention deficit/hyperactivity disorder (ADHD)]. Results: In 2002–2003, antidepressants were prescribed in 4.1 million (36.1%) visits, followed by 3.2 million (28.8%) visits in 2004–2005 and 2.8 million (26.8%) visits in 2006–2007. However, antidepressant prescribing patterns reversed during 2008–2009, with an increase to 3.6 million (32.5%) visits. Compared to the period preceding the FDA boxed warning (2002–2003), a significant decline in visits related to antidepressant prescribing detected in the immediate post-FDA boxed warning period (2006–2007) (AOR ¼ 0.67, 95% CI: 0.47–0.96). No association between the FDA boxed warning and antidepressant prescribing visits was detected during the FDA boxed warning period (2004–2005) (AOR ¼ 0.80, 95% CI: 0.53–1.21) and in the late post-FDA boxed warning period (2008–2009) (AOR ¼ 1.01, 95% CI: 0.63–1.60). Conclusions: After a 2-year lag period, antidepressant prescribing for visits of children and adolescents diagnosed with depression or other psychiatric disorder(s) in community-based and outpatient clinic * Corresponding author. Tel.: þ1 847 935 9190, þ1 917 379 3390 (mobile); fax: þ1 847 937 1992. d I ‘Manish Mittal’ am currently an employee of the Abbvie. However, during the conduct of this research I was a doctoral student at the OUHSC. Abbvie is in no manner associated with this research. E-mail address: [email protected], [email protected] (M. Mittal). 1551-7411/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.sapharm.2013.11.001

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settings declined when compared to the period preceding the FDA boxed warning. This decline was not sustained in the period of five years after implementation of the FDA boxed warning. Ó 2013 Elsevier Inc. All rights reserved. Keywords: Depression; Antidepressant; FDA boxed warning; Suicidality; Children and/or adolescents

Introduction Approximately one-half of the antidepressantrelated visits for children and adolescents in the United States are for off-label indications including attention deficit/hyperactivity disorder (ADHD) and anxiety disorders.1,2 Moreover, only 12 of the 32 antidepressant medications have been approved by the U.S. Food and Drug Administration (FDA) for depression, obsessive-compulsive disorder (OCD), or nocturnal enuresis disorder in children/adolescents 6–17 years of age.3 Despite limited official labeling, antidepressant use among children and adolescents increased from 1.6% in 1998 to 2.4% in 2002.4–7 Antidepressant medication use in children and adolescents received significant attention in 2003 when the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA), and the FDA reported a direct association between antidepressant use and risk of suicidality (i.e., suicidal ideation, behavior, or attempts) in pediatric patients.8,9 Following this report, the FDA recommended “close observation of adults and pediatric patients” treated with antidepressants for the emergence of suicidality10 in March 2004. After an analysis of 24 antidepressant trials demonstrated an increased risk of treatmentemergent suicidal behavior in pediatric populations [relative risk (RR) ¼ 1.95, 95% CI ¼ 1.28–2.98],11,12 the FDA mandated a boxed warning for all antidepressants, describing an increased risk of suicidality in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders3 in October 2004. A recent observational study reinforced the decision of the FDA to include all antidepressants in the boxed warning by demonstrating equal event rates among all antidepressants.13 Importantly, the boxed warning did not forbid the use of antidepressant in children and adolescents, but rather cautioned physicians and caregivers to closely monitor children and adolescents using antidepressants as some patients need them when there is no other safer alternative available. In contrast with the FDA opinion, there are general practice guidelines that recommend the use of antidepressant in the treatment of

childhood anxiety disorders14 or use as an adjunct or second-line therapy for ADHD when symptoms remain after initiation of first-line therapy of stimulants.15 Expert panels from the American Academy of Child and Adolescent Psychiatry (AACAP), the American Psychiatric Association (APA) and the American College of Neuropsychopharmacology (ACNP) have remained supportive of the use of antidepressants in children and adolescents and argue that the benefits from the medications outweigh the risks.16,17 Additionally, a number of research studies have suggested antidepressant use decreases the suicide rate among children and adolescents.18–21 The conflicting guidance between regulatory agencies and professional societies may confuse providers as to appropriate use antidepressants in children. Following the FDA boxed warning, numerous studies observed not only a short-term reduction in antidepressant treatment, but also a reduction in diagnosis of depression in the pediatric population.22–33 Although there was an unexpected increase in national suicide rates by 8% from 2003 to 2004 among children and adolescents,34 some experts believe that it may be premature to draw conclusions based on year-to-year fluctuations in antidepressant prescriptions and youth suicide.35 Still, these corresponding trends of a decline in antidepressant treatment and an increase in suicide rate among youth have raised public health concerns.36 Research to date that has assessed the association between the FDA warning and antidepressant prescribing in children and adolescents has primarily focused on specific population subgroups, such as those with only a depression diagnosis25– 27,31 ; used data sources that are relatively narrow in scope, such as prescription claims data25–29; examined antidepressant patterns over a short time period after the FDA boxed warning (from Oct 2004 up to 2007)22–28,30–33; or did not collectively account for the wide array of patient and physician characteristics that may influence antidepressant prescribing.25–29 While Chen et al24 used nationally-representative data to describe antidepressant prescribing patterns in youths, they did

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not adjust for important background patient and physician visit characteristics. This study further informs research to date by evaluating a broader range of psychiatric disorders using a larger, nationally-representative sample of visits to outpatient settings over a longer period allowing for assessment of immediate and sustainable effects of the boxed warning on prescriber behavior. Therefore, the primary objective of this study was to describe antidepressant prescribing among children and adolescents who have been diagnosed with depression or other psychiatric disorder(s) (anxiety disorders or ADHD) in outpatient settings from 2002 to 2009 by using a national sample of physician visits, before and after the introduction of the FDA boxed warning, while adjusting for important patient and physician visit characteristics not considered in previous research. Methods Study design and data source Cross-sectional data from both the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) between the years 2002–2009 were used.18 These surveys include data abstracted from medical records and are conducted annually by the Centers for Disease Control and Prevention (CDC) using a national, multistage, probability-

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based sample of physician office and outpatient department visits to assess ambulatory health care utilization in the US. No emergency department visits recorded in the NHAMCS were included. Data are collected in a manner that allow the results to be extrapolated to national practice patterns after weighting and accounting for sampling design. The sampling strategy and data collection methods are described in greater detail elsewhere.37,38 This research was determined as exempt from The University of Oklahoma Health Sciences Center Institutional Review Board because it uses publicly available, deidentified data. Inclusion and exclusion criteria The combined NAMCS and NHAMCS data sample for 2002–2009 included 496,912 physician visits (Fig. 1). A final analytical sample of 4035 physician visits was selected by including visits of children and adolescents from 6 to 17 years of age, diagnosed with depression or other psychiatric disorders (anxiety disorders or ADHD) as indicated by International Classification of Diseases, 9th Revision, Clinical Modification (ICD9-CM)39,40 codes (Table 1). Study variables The dichotomous dependent variable was defined by physician visits in which “at least” one

Fig. 1. Inclusion and exclusion criteria.* No emergency department visits recorded in the NHAMCS were included.

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Table 1 Depression or other psychiatric disorders [anxiety disorders or attention deficit/hyperactivity disorder (ADHD)] as indicated by International Classification of Diseases, 9th Revision, Clinical Modification (ICD9-CM) codes Diagnostic group

Categories (ICD-9 CM codes)

I. Depression

(a) Major depressive disorder (296.2x, 296.3x) (b) Dysthymic disorder (300.4) (c) Depressive disorder not elsewhere specified (311)

II. Other psychiatric disorder(s) (1) Anxiety disorders

(2) Attention deficit/ hyperactivity disorder (ADHD)

(a) Anxiety disorder (300.0x) (b) Unspecified phobia (300.20) (c) Agoraphobia with panic disorder (300.21) (d) Social phobia (300.23) (e) Other specific phobia (300.29) (f) Obsessive-compulsive disorders (300.3) (g) Posttraumatic stress disorder (309.81). (a) With hyperactivity (314.00) (b) Without hyperactivity (314.01)

antidepressant [selective serotonin reuptake inhibitors, tricyclic and related antidepressants, selective serotonin norepinephrine reuptake inhibitors, or miscellaneous antidepressants (i.e., trazodone, bupropion, nefazodone, and mirtazapine)37,38] was or was not prescribed. Antidepressant-related visits may have included prescription of more than one antidepressant. The study time period was divided into four, 2-year intervals (i.e., 2002– 2003, 2004–2005, 2006–2007, 2008–2009), and to more explicitly account for the periods immediately before, during, and after the issuance of the FDA boxed warning as well as sustained effects up to 5 years post-warning. The selection of covariates was guided by the Andersen Behavioral Model for Access to Medical Care and included predisposing (i.e., individuals’ propensity to use services), enabling (i.e., individuals’ ability to access services), and need (i.e., illness level) factors that have been shown to influence the use of health services.41 Predisposing characteristics included pediatric age group, sex, race, and ethnicity. Age was categorized as children 6–11 years of age and adolescents 12–17 years of age. Race was grouped as White, Black, or Other (i.e., Asian, Native

Hawaiian/Other Pacific Islander, American Indian/Alaska Native, multiple races). Ethnicity was categorized as Hispanic or non-Hispanic. Enabling characteristics included geographical region, and metropolitan statistical area (MSA) status. Geographical region was categorized as Northeast, Midwest, South, or West. To control for physician visits in both rural and urban settings, visits were dichotomized as to whether or not they occurred within an MSA. Need characteristics included major reason for visit, physician’s diagnosis of depression or other psychiatric disorder(s), presence of chronic condition, and non-pharmacological mental health treatment. The major reason for visit included acute, chronic (i.e., routine or flare up), or preventive care. A four-level indicator variable for depression or other psychiatric disorder(s) was created by assessing whether a particular visit involved depression only, anxiety disorders only, ADHD only, or a combination of psychiatric disorder(s) including depression, anxiety disorders and/or ADHD. All four diagnosis categories were mutually exclusive. An indicator variable for the current diagnosis of at least one chronic condition was created from a list of four chronic conditions (i.e., asthma, cancer, diabetes mellitus and obesity)42 using the first three digits for each of the three ICD-9-CM diagnosis codes reported at the visit. These comorbidities are some of the more common chronic conditions in children and are often associated with depression, which may influence the antidepressant prescribing among children and adolescents. Non-pharmacological mental health treatment only included psychotherapy, which was consistently collected throughout the study period and indicated whether or not psychotherapy was ordered or provided during the visit. Data analysis Univariate descriptive statistics were used to profile all study variables. Proportions across time periods were compared using designed-based F statistic. Bivariable and multivariable logistic regression analyses were used to estimate and report unadjusted and adjusted odds ratios (ORs), respectively, that described visits of antidepressant prescribing during the FDA boxed warning (2004–2005), immediate post-FDA boxed warning (2006–2007), and late post-FDA boxed warning (2008–2009) when compared to the period preceding the warning (2002–2003). Multicollinearity was assessed between all covariates and no evidence

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was identified; therefore the analytical model was adjusted for all predisposing, enabling, and need characteristics, including diagnoses of depression or other psychiatric disorder(s). For all analyses, the a-priori alpha level was set to P-value %0.05. All data management and analyses were performed in PC SAS 9.2 (SAS Institute Inc., Cary, NC) using complex survey commands with Taylor-linearized variance estimation sampling weights and masked sampling design variables provided in the NAMCS/NHAMCS dataset to provide population estimates. Results Overall, the analytical sample included 4035 physician visits representing a study population of almost 44.4 million (44,376,778) office-based and hospital outpatient department (OPD) visits by US children and adolescents aged 6–17 years diagnosed with depression or other psychiatric disorder(s) during 2002–2009 survey years. Henceforth, the results are presented and discussed at the population level. In the study population, a larger proportion of visits were contributed by adolescents (53.7%) when compared to children 6–11 years of age. Physician visits involved patients who were predominantly male (65.8%), White (84%), and nonHispanic (92.4%). The majority of visits involved children and adolescents diagnosed with ADHD only (67.4%). Physician visits were distributed similarly across each of the study periods (i.e., 11.3 million visits in 2002–2003, 11.2 million visits in 2004–2005, 10.6 million visits in 2006–2007, and 11.3 million visits in 2008–2009). Baseline predisposing, enabling, and need characteristics of physician visits diagnosed with depression or other psychiatric disorder(s) within each level of consecutive two-year time period are described in Table 2. Baseline characteristics did not differ by the time period before and after the introduction of the FDA boxed warning. As Table 3 depicts, 13.7 million (31.1%) of all visits included an antidepressant prescription. In 2002–2003, antidepressants were prescribed in 4.1 million (36.1%) visits, followed by 3.2 million (28.8%) visits in 2004–2005 and 2.8 million (26.8%) visits in 2006–2007. A pattern of gradual decline in antidepressant prescribing which reversed in 2008–2009 with 3.6 million (32.5%) visits resulting in an antidepressant prescribed. To quantify the association between visits with prescribing an antidepressant and implementation

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of the FDA boxed warning, unadjusted and adjusted ORs were reported as shown in Table 3. Compared to the period preceding the FDA boxed warning (2002–2003), there was no change in the likelihood of antidepressant prescribing in overall visits for depression or other psychiatric disorder(s) visits during the FDA boxed warning period (2004– 2005) (AOR ¼ 0.80, 95% CI: 0.53–1.21). A significant decline in visits resulting in antidepressant prescribing was detected in the immediate post-FDA boxed warning period (2006–2007) (AOR ¼ 0.67, 95% CI: 0.47–0.96) when compared to pre-FDA boxed warning period (2002–2003). However, this significant association was not observed in the late post-FDA boxed warning period (2008–2009) (AOR ¼ 1.01, 95% CI: 0.63–1.60). Discussion This study confirms previous research24–28,33 that reported the FDA boxed warning was associated with a reduction in prescribing antidepressants in pediatric patients for a brief period of time immediately after it was issued. After adjusting for psychiatric disorders and other covariates, the odds of antidepressant prescribing in the immediate post-FDA boxed warning (2006–2007) were significantly decreased by 33% at physician visits for depression or other psychiatric disorder(s) when compared to the period preceding the warning (2002–2003) [Table 3]. The antidepressant prescribing pattern that appears to decline in the immediate postwarning (2006–2007) was not sustained through the late post-warning period (2008–2009), approximately five years after the FDA boxed warning. Several conclusions may be drawn from these results: (1) tempering of the impact of the warning; (2) increased use of perceived safer treatment alternatives. Previous research reported that key health messages in the FDA boxed warning was not sufficiently communicated to the public through widespread media coverage that could also affect the prescribing patterns immediately after a safety warning.43–45 Although the impact of media coverage was not studied, based on findings from this research, it did not appear to remain influential over time. Also, this study did not detect a significant change in antidepressant prescribing patterns during the FDA boxed warning (2004–2005) suggesting an expected lag in dissemination and uptake of the warning.46 Although similar in some respects, the research reported herein differs from past research on this

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Table 2 Population descriptive analysis: depression or other psychiatric disorder(s) related physician visits of children and adolescents of age 6–17 years from 2002 to 2009 (N ¼ 44.4 million) Characteristics

Categories

2002–2003 n ¼ 11.3 million (%)

2004–2005 n ¼ 11.2 million (%)

2006–2007 n ¼ 10.6 million (%)

2008–2009 n ¼ 11.3 million (%)

P-valuea

Age group

6–11 years 12–17 years Male White Black Others Hispanic Acute Chronic Preventive Depression Anxiety ADHD Multiple Yes Yes Northeast Midwest South West Non-MSA

5.2 6.1 7.5 9.7 1.4 0.2 0.6 1.4 9.1 0.8 1.8 0.9 7.1 1.5 0.2 3.4 2.3 2.7 5.2 1.1 1.6

5.1 6.1 7.9 9.2 1.5 0.5 0.7 1.6 8.0 1.6 1.4 0.9 7.8 1.1 0.4 2.6 2.3 2.4 4.8 1.7 1.2

5.1 5.5 6.8 8.8 1.3 0.5 0.9 1.4 7.7 1.5 1.3 0.8 7.4 1.1 0.4 2.3 1.8 2.7 4.2 1.9 1.7

5.1 6.2 7.1 9.5 1.5 0.3 1.1 1.5 8.1 1.7 1.2 1.1 7.6 1.4 0.5 2.2 2.1 3.9 4.3 1.0 1.7

0.9123

Sex Race

Ethnicity Major reason for visit

Depression/other psychiatric disorder(s)

Chronic condition Psychotherapy Geographical region

Metropolitan area

(45.8) (54.2) (66.3) (86.2) (12.2) (1.6) (5.7) (12.3) (80.6) (7.1) (16.1) (7.4) (63.3) (13.2) (1.7) (30.1) (20.4) (23.6) (45.9) (10.2) (14.5)

(45.5) (54.5) (70.1) (81.9) (13.7) (4.4) (6.2) (13.8) (71.4) (14.8) (12.1) (7.8) (69.6) (10.6) (3.5) (22.9) (20.2) (21.8) (43.0) (15.0) (10.2)

(48.3) (51.7) (64.1) (82.8) (12.8) (4.4) (8.5) (13.5) (72.6) (13.9) (12.6) (8.1) (69.5) (9.9) (3.3) (21.6) (17.1) (25.1) (39.6) (18.2) (16.0)

(45.5) (54.5) (62.7) (84.9) (12.9) (2.2) (10.2) (12.9) (72.3) (14.8) (10.6) (9.4) (67.2) (12.8) (4.1) (19.9) (18.5) (34.2) (38.3) (8.9) (14.7)

0.2336 0.5444

0.4392 0.2420

0.6930

0.4140 0.3162 0.2830

0.6633

ADHD ¼ attention deficit/hyperactivity disorder; MSA ¼ metropolitan statistical area. The analytical sample of 4035 physician visits representing a study population of almost 44.4 million (44,376,778) office-based and hospital outpatient department (OPD) visits. a P-value were based on the designed-based F statistic.

topic. Kurian et al28 detected a significant decline (31%) in antidepressant prescribing, similar to our results, after the FDA boxed warning. However, they included a very select subgroup of the state Medicaid population, which may limit its

application to the general US population. Whereas, the research reported herein employed data from NAMCS and NHAMCS which can be generalized to a nationally-representative pediatric population, enabling the evaluation of national ambulatory

Table 3 Unadjusted and adjusted national estimates for the odds of prescribing antidepressants by year in overall visits related to depression or other psychiatric disorder(s) while adjusting for important patient and physician visit characteristics (N ¼ 44.4 million) Characteristics

Time period

Categories

2002–2003 2004–2005 2006–2007 2008–2009

Antidepressant visits Unweighted n (row%)

Weighted n (in millions) (row%)

484 362 313 294

4.1 3.2 2.8 3.6

(45.6) (37.4) (29.4) (31.3)

(36.1) (28.8) (26.8) (32.5)

Unadjusted OR

Adjusted ORa

Referent 0.71 (0.49–1.05) 0.65 (0.45–0.93)* 0.85 (0.57–1.28)

Referent 0.80 (0.53–1.21) 0.67 (0.47–0.96)* 1.01 (0.63–1.60)

Bivariable and multivariable logistic regression analyses were used to estimate and report unadjusted and adjusted odds ratios (OR) respectively. *P ! 0.01 a Adjusted for age group, sex, race, ethnicity, major reason for visit, psychiatric disorder, chronic condition, psychotherapy, geographical region and metropolitan area.

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care prescribing patterns. While Chen et al24 also utilized NAMCS and NHAMCS data between 1998 and 2007 and observed that antidepressants prescribed at physician visits decreased after the FDA boxed warning, they did not account for potential confounders that may distort the association between antidepressant prescribing and the FDA boxed warning. Thus, the current study extends the work of Chen et al by examining the immediate and sustainable effect of the boxed warning till 2009 using multivariable models to control for potential factors associated with antidepressant prescribing. Valluri et al25 and Libby et al26,27 have assessed the association of the FDA boxed warning in patients with new-onset depression diagnosis only. In contrast, this research examined the association in visits for several other psychiatric disorders in addition to depression. Finally, Singh et al33 reported a decrease in the use of antidepressants for depressive or anxiety disorders after the FDA boxed warning. However, all data were collected from a single outpatient clinic and therefore minimizing external validity. The long-term result of this study differs from Clarke et al29 who reported a continuous decline in antidepressant filling among depressed pediatric patients through 2009. A potential reason for conflicting results is that Clarke and colleagues used prescription claims data, indicating filled antidepressant medication and representing both physician and patient behavior. The NAMCS/ NHAMCS data represent prescriber-only behavior. There was a potential for pediatric patients to have been prescribed an antidepressant medication in the late post-warning period (2008–2009), but their caregivers did not fill the prescription either intentionally or unintentionally.33 Another reason for different results could be the selected analytical sample. Compared to pre-warning period, the likelihood of prescribing an antidepressant in visits for anxiety and/or ADHD may have remained unchanged in the late post-warning period (2008–2009) due to less risk of suicidality for anxiety and ADHD, which is more often associated with depression.10,47 Because ADHD diagnosis was not considered by Clarke et al,29 which represent a disproportionally large proportion of visits for each time period studied in this research, any potential effect on antidepressant prescribing in visits for depressed patients may have been masked due to the rather large diagnosis group size imbalance. Compared to prior work, this study has several strengths that must be considered. Though

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antidepressants are prescribed in several behavioral disorders, this study selected the diagnosis of depression, ADHD, and anxiety disorders, which represent the most frequently associated diagnoses (O80%) with off-label antidepressant prescribing patterns among children and adolescents in the US.1 The current study detected a significant decline in antidepressant prescribing after evaluating a broader range of psychiatric disorders, not considered in previous studies. Since the use of insurance claims precludes the inclusion of certain important covariates in previous analyses,5–29 the number and type of potential confounding factors simultaneously considered in the current study is also a strength of this research. No previous studies have included the full range of potential factors considered in this research, many of which are considered important potential confounders (i.e., race/ethnicity or presence of chronic conditions) in antidepressant prescribing as suggested in earlier studies.48–50 Furthermore, the inclusion of data for an extended period of time (2002–2009), grouped into four time periods, allowed for the evaluation of the sustained association of the FDA warning over a longer period of time. Finally, this study used data from NAMCS and NHAMCS that represent prescriber-only behavior, allowing for the assessment of actual prescribing behavior or intent of ambulatory care physicians. In contrast, prior research using claims data incorporates both prescriber and patient behavior. This study also has important limitations to consider. Although the safety concerns initially rose in June 2003, this study considered 2002–2003 as a pre-warning period consistent with the methodology used by Chen et al.24 The slight overlap would likely bias the results toward the null. There may be several other factors, including advertising by pharmaceutical manufacturers, communications by other government agencies and media reports that could affect the antidepressant prescribing in children during that period. These factors, however, could not be accounted for in this study. Bipolar disorder is associated with offlabel antidepressant prescribing patterns among youth in the US1,51,52; however, this study did not include bipolar-related visits in the analytical sample because the use of antidepressants in bipolar disorder is controversial and is potentially associated with a higher risk of mania or could lead to mood destabilization.53,54 Approximately 40% of observations with missing information from at least one factor were excluded from multivariable

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analyses. This potential measurement error was minimized by confirming no differences in antidepressant prescribing pattern between visits of missing versus complete information. No information about new antidepressant prescription was collected during the study period. In NAMCS, physician specialty was categorized into 15 specialty groups and in NHAMCS, outpatient clinics were categorized into six specialty groups. Because of different categorization, physician specialty could not be adjusted in the analysis. The study population was not stratified by individual diagnostic groups because of reduced statistical power. Therefore, this limits the study’s ability to determine if there is a significant change in antidepressant prescribing across the disease areas included. Another limitation arises because the ‘depression or other psychiatric disorder(s)’ variable was created and identified based on a maximum of three ICD-9 diagnosis codes most relevant to the given visit provided in the dataset. This may result in the possibility of under-identification of the diagnoses of depression or other psychiatric disorder(s). Finally, because the NAMCS and NHAMCS records data from visits rather than individual patients, it is possible that more frequent users of care are oversampled. Conclusion The FDA-issued boxed warning for antidepressant prescribing in children and adolescents encourages prescribers to balance between risk and clinical need. It appears that after a 2-year lag period, the FDA boxed warning was briefly associated with a reduction in the prescribing of antidepressants for children and adolescents diagnosed with depression or other psychiatric disorder(s) in a communitybased and outpatient clinic settings, after adjusting for predisposing, enabling, and need characteristics. However, this decline was not sustained five years after the FDA boxed warning. Future study is required to examine the impact of the FDA boxed warning on individual diagnostic groups. Acknowledgments No financial or material support was received by any of the authors in the conduction of this research or the preparation of this manuscript. The primary author had full access to the publicly available NAMCS/NHAMCS data and assumes full responsibility for the integrity and accuracy of the analysis.

The authors thank Tracy Hagemann, Pharm.D., Clinical Pediatric Specialist, for assistance with the concept generation, Barbara Neas, Ph.D., Professor of Biostatistics and Epidemiology, for guidance in data analysis, and Linda Cowan, Ph.D., Professor of Biostatistics and Epidemiology, for guidance in interpreting the results. References 1. Lee E, Teschemaker AR, Johann-Liang R, et al. Off-label prescribing patterns of antidepressants in children and adolescents. Pharmacoepidemiol Drug Saf 2012;21:137–144. 2. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. N Engl J Med 2001;344:1279–1285. 3. United States Food and Drug Administration. Suicidality in Children and Adolescents Being Treated With Antidepressant Medications, Oct 15, 2004. http://www.fda.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatientsandProviders/Drug SafetyInformationforHeathcareProfessionals/Public HealthAdvisories/ucm161679.htm. Accessed 01.07.13. 4. Delate T, Gelenberg AJ, Simmons VA, Motheral BR. Trends in the use of antidepressants in a national sample of commercially insured pediatric patients, 1998 to 2002. Psychiatr Serv 2004;55: 387–391. 5. Ma J, Lee KV, Stafford RS. Depression treatment during outpatient visits by U.S. children and adolescents. J Adolesc Health 2005;37:434–442. 6. Zito JM, Safer DJ, DosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157:17–25. 7. Olfson M, Marcus SC, Weissman MM, Jensen PS. National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry 2002;41:514–521. 8. United Kingdom Medicines and Healthcare Products Regulatory Agency. Safety of Seroxat (paroxetine) in Children and Adolescents Under 18 years, June 10, 2003. http://www.mhra.gov.uk/Safety information/Safetywarningsalertsandrecalls/Safety warningsandmessagesformedicines/CON2015704. Accessed 01.07.13. 9. United States Food and Drug Administration. Reports of Suicidality in Pediatric Patients Being Treated With Antidepressant Medications for Major Depressive Disorder (MDD), Oct 23, 2003. http:// www.fda.gov/Drugs/DrugSafety/PostmarketDrug SafetyInformationforPatientsandProviders/Drug SafetyInformationforHeathcareProfessionals/Public HealthAdvisories/ucm168828.htm. Accessed 01.07. 13. 10. United States Food and Drug Administration. Worsening Depression and Suicidality in Patients

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12.

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14.

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16.

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18.

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21.

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